tbuckley/cabot-search huggingface dataset:
DDEL-04. Pharmacokinetic/Pharmacodynamic analysis of the DNA methyltransferase inhibitor 5-azacytidine shows adequate brain tissue penetration with intravenous administration in a DIPG mouse patient-derived xenograft model.
Authors: Andrew Groves, Kristen Jones, Amy Cameron, Eshini Panditharatna, Murry Morrow, Brett Mozarsky, Cynthia McCully, Cody Peer, Quang- De Nguyen, Mariella Filbin, Katherine Warren
Journal: Neuro-Oncology (2022)

Abstract One of the biggest obstacles in developing effective therapies for CNS tumors is drug delivery due to the enigmatic challenge of penetrating the blood-brain barrier. 5-azacytidine is a DNA methyltransferase inhibitor which was the first epigenetic targeting chemotherapeutic approved by the FDA. Altered DNA methylation is a hallmark of many cancers, including diffuse intrinsic pontine glioma (DIPG). 5-azacytidine has been shown to be active in DIPG cell lines, with only modest in-vivo activity. We have previously shown in a non-human primate model that intravenous (IV) administration of 5-azacitidine does not result in measurable CSF penetration, while intrathecal (IT) administration does and is well tolerated. To follow up these studies in a tumor-bearing mouse model (HSJD DIPG007), we performed pharmacokinetic (PK) and pharmacodynamic (PD) analysis following IV vs. IT administration. Forty mice were randomized to receive four weekly doses of IV 5-azacytidine (25 mg/kg), IT 5-azacytidine (40 μg), or corresponding vehicle controls. Four mice from each arm were sacrificed 30 minutes after the last dose and brain tissue was collected for PK/PD analysis. Drug concentration was quantified using ultra-high-performance liquid chromatography with tandem mass spectrometric detection, while pharmacodynamic methylation profiling was performed using the Infinium MethylationEPIC BeadChip (850K). Brain tissue concentrations were comparable between IV (7.6-58.0 pg/mg) and IT (6.9-63.9 pg/mg) dosing. Methylation profiling unexpectedly showed a significantly more pronounced pharmacodynamic effect with IV dosing vs. IT, with a mean decrease of 13.6% vs. 2.6% in global DNA methylation score (GDMS = percentage of highly methylated (beta ≥ 0.7) genomic loci) compared to vehicle controls. For the remaining mice, there was no significant difference in survival. Our results are encouraging that phenotypically relevant demethylating effects can be achieved in the CNS with IV 5-azacytidine administration; however, further research is needed to develop promising combination strategies in DIPG.
Report on microbial and resistance patterns of the causative pathogens of nosocomially-acquired urinary tract infections: Preliminary data analysis of the GPIU-Studies 2015-2020
Authors: J.F. Alidjanov, C. Ifland, F. Ifland, G. Sass, J. Medina-Polo, A. Magyar, T. Perepanova, F. Bruyère, A. Pilatz, T. Cai, J. Abdusalamov, E. Kulchavenya, Z. Tandogdu, B. Köves, B. Wullt, R. Bartoletti, G. Bonkat, K.G. Naber, F.M.E. Wagenlehner, T. Bjerklund-Johansen
Journal: European Urology (2022)
Risk and predictors of ipilimumab-associated cardiac adverse events among patients treated for melanoma: A national cohort analysis.
Authors: Muhieddine Labban, Elio Adib, Bjoern Langbein, Xi Chen, David-Dan Nguyen, Alexander P Cole, Stuart R. Lipsitz, Maxine Sun, Quoc-Dien Trinh
Journal: Journal of Clinical Oncology (2022)

e14592 Background: Ipilimumab is a CTLA-4 inhibitor widely used to treat advanced melanoma. While ipilimumab-induced cardiac immune-related adverse events (irAE) have been reported, there is a paucity of data from large cohorts. We investigated the risk and predictors of ipilimumab-associated cardiac irAE in a national cohort of patients with cutaneous melanoma. Methods: Using SEER-Medicare linked data, we compared the risk of cardiac irAE between patients treated with ipilimumab with or without concomitant treatment for cutaneous melanoma and controls not treated with ipilimumab following a primary diagnosis of cutaneous melanoma. We excluded patients ≤65 years and patients with cardiac comorbidities diagnosed within one year prior to the initiation of melanoma treatment. The primary endpoint was the incidence of at least one cardiac irAE after ipilimumab initiation including acute pericarditis, myocarditis, cardiomyopathy, conduction disorders, cardiac dysthymias, acute heart failure, and takotsubo syndrome. To estimate the risk of cardiac irAE, we conducted a multivariable competing-risk analysis adjusting for death of any cause within one year of treatment as a competing event. Then, we constructed a stepwise logistic regression to assess the predictors of having at least one cardiac irAE within one year of ipilimumab initiation. Subgroup analysis was conducted among patients who received ipilimumab only. The models were adjusted for patient demographics, disease stage, Charlson comorbidity index (CCI), history of hypertension, autoimmune disease, end stage renal disease (ESRD), chronic anticoagulant, and steroid use. Results: The cohort included 715 patients treated with ipilimumab and 22,070 controls. In the ipilimumab arm, 23.4% had metastatic disease, 9.5% had a history of autoimmune disease, and 2.2% had CCI≥2. The incidence rates of cardiac irAE among patients who received ipilimumab and among the control group were 23.3 and 13.6 per 1,000 person-years, respectively. We found that patients who received ipilimumab had a higher risk of cardiac irAE compared to controls (adjusted hazard ratio 1.87; 95%CI 1.50-2.32; p &lt; 0.001). In addition to ipilimumab treatment, other predictors of cardiac irAE included male gender, older age, patients with metastatic disease, history of autoimmune disease, hypertension, ESRD, anticoagulant use, and CCI≥2. The predictors of cardiac irAE were also consistent in the subgroup analysis of patients who received ipilimumab only. Conclusions: Patients who received ipilimumab with or without concomitant treatment for cutaneous melanoma had a higher risk for cardiac irAE. Predictors of cardiac irAE help tailor therapy according to patients’ risk profiles.
Another Rescue Therapy Option for Patients with Moderate-to-Severe Asthma
Authors: Michael Schatz
Journal: New England Journal of Medicine (2022)

Since the initial guidelines of the National Asthma Education and Prevention Program (NAEPP) were published in 1991,1 short-acting β2-agonists (SABAs) have been recommended as the preferred rescue therapy for patients with asthma of any severity. In the 2020 NAEPP update,2 for the first time, two additional forms of rescue therapy were recommended: an as-needed SABA inhaler paired with a separate inhaled glucocorticoid for patients with mild asthma and a single inhaler containing glucocorticoid–formoterol for patients receiving maintenance therapy with an inhaled glucocorticoid–formoterol combination (single maintenance and reliever inhaler therapy [SMART]) for moderate-to-severe asthma. In this issue of the Journal, Papi . . .
Complete evaluation of resistance mechanisms to first-line osimertinib requires tissue biopsy.
Authors: Zofia Piotrowska, Andrew Piper-Vallillo, Mandeep Banwait, Yin P Hung, Revati Rao, Alona Muzikansky, Catherine Belle Meador, Aaron N. Hata, Lecia V. Sequist
Journal: Journal of Clinical Oncology (2022)

e21154 Background: Osimertinib (osi) is the preferred 1 st line (1L) therapy for patients (pts) with EGFR-mutant NSCLC, but acquired resistance is universal. Identification of mechanisms of resistance (MoR) to 1L osi can inform subsequent treatment strategies. Here, we report MoRs identified at our institution from tissue and/or liquid biopsy (bx) upon 1L osi progression. Methods: We included pts seen at MGH with advanced EGFR+ NSCLC who had tissue and/or liquid bx (for ctDNA analysis) obtained at progression on 1L osi. Molecular testing was performed using local next-generation sequencing (NGS) and, when available, MET/ EGFR FISH. We retrospectively collected clinical characteristics, tissue histology and NGS results. Results: 54 pts (38 Female; median age 61 yrs) had tissue (n = 35) and/or liquid (n = 32) bx upon progression on 1L osi between November 2016-January 2022. 13/54 pts had both tissue and ctDNA testing. Primary EGFR mutations included del19 (32), L858R (16) and other (6). Median time from osi start to 1st resistance bx was 12.3 mos (range, 1-37). MoRs are summarized in the table. Among 35 pts with tissue bx, histologic transformations (trans) were the most common MoR, seen in 23% pts, including both small cell histology (tSCLC; 5/35), squamous histology (tSqCC; 2/35) and 1 pt with both SCLC + SqCC features in one bx. Among 5 pts with tSCLC and pre-trans NGS, only 2 had baseline TP53/RB1 loss. MET amp was seen in 20% tissue (including one with tSqCC) and secondary EGFR mutations in 9%; 43% of tissue bx had no identified MoR. Among 32 pts with ctDNA NGS, secondary EGFR mutations (16%) were the most prevalent MoR, with MET amp seen in 13%. 65% pts had no MoR by ctDNA. 6/13 pts with both tissue and ctDNA had concordant findings (MET amp-2, EGFR L718Q – 1; No MoR - 3). As expected, the 2 pts with tSCLC had no MoR in ctDNA. In 2 cases, MET amp was seen in tissue but not ctDNA; the converse was true in 1 pt. Conclusions: Histologic transformations were the most common MoR to first-line osimertinib accounting for 23% tissue biopsies and, in 3/5 pts, occurred in the absence of the known risk factor of baseline TP53/RB1 loss. In this small cohort, MET amp was more commonly seen in tissue than in ctDNA, and 63% of liquid biopsies showed no detectable MoR. Our findings suggest that tissue biopsy is critical for complete evaluation of MoRs in pts progressing on first line osimertinib, and that tissue and ctDNA may be complementary.[Table: see text]
EPID-08. Epidemiology of childhood brain tumors in Morocco
Authors: Ouassima Erefai, Amal Haimer, Faouzi Habib, Abdelmajid Soulaymani, Abdelrhani Mokhtari, Hinde Hami
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Brain tumors are the most common solid tumors and cause of cancer-related death in children less than 15 years of age. However, little is known about these tumors in Morocco. The aim of this study is to describe the epidemiological features of pediatric brain tumors in Morocco. METHODS: This is a descriptive retrospective study of pediatric brain tumor cases, diagnosed and treated between 1994 and 2015 at Al Azhar Oncology Center in Rabat. Patient’s age and sex, habitat area, overall survival and tumor characteristics were evaluated. RESULTS: During the study period, 41 children under the age of 15 years were diagnosed with brain tumors at Al Azhar Oncology Center. Brain tumors were more common among boys than girls, with a male-female ratio of 1.9. The average age of diagnosis was 7.47 ± 3.06 years (range 2-14 years). More than half (51.22%) of the cases were diagnosed in children aged 5-9 years. Regarding the habitat area, nearly two-thirds (62.50%) of children live at least 30 kilometer (km) away from the cancer center. Medulloblastoma was the most common tumor type with 34.15% of cases. Overall, one patient develops a metastasis. Among the cases for whom the outcome was known, five children died during the study period, consisting of three girls and two boys. CONCLUSIONS: Children’s brain tumors remain a serious public health problem in Morocco, especially with the limited number of specialized pediatric cancer centers. The travel burden is a significant factor affecting access to appropriate diagnosis and treatment and can impede the provision of high-quality care for cancer patients.
SURG-13. The COMBAT Project - Core post operative morbidity set for paediatric brain tumours
Authors: Sandhya Trichinopoly Krishna, Christopher Millward, Conor Mallucci, Carrol Gamble, Michael Jenkinson, Barry Pizer
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Brain tumours are associated with high morbidity both from the tumour and the medical and surgical interventions used to treat them. Post operative morbidity reporting following surgery for paediatric brain tumours is poor due to the lack of a common language when reporting harms. One solution is to develop a core adverse outcome set to stipulate the minimum post operative harms that should be reported. The COMBAT (Core post operative morbidity set for paediatric brain tumours) Project will develop a core adverse outcome set that can be applied to post operative paediatric brain tumour patients to harmonise how harms are measured and reported, enabling comparison between different trials, studies and clinical services. We aim to generate interest in the COMBAT Project and invite collaboration with healthcare professionals and researchers experienced in paediatric neuro oncology surgery. METHODS AND ANALYSIS : A systematic review will identify harms reported in post operative paediatric brain tumour patients and how they are measured. We will engage with national and international stakeholders including healthcare professionals, researchers, patients and their carers. Qualitative interviews with patients and carers will identify any important harms not extracted in the systematic review. A Delphi survey will be created from the harms identified. An international consensus meeting will be held to finalise the core adverse outcomes set. The final core adverse outcome set will be published and disseminated to encourage uptake. DISCUSSION: There is a clear need for a common language to harmonise measurement and reporting of harms following surgery for paediatric brain tumour patients. The core adverse outcome set will be developed with collaboration with key stakeholder groups to ensure it is representative. It will be used to standardise surgical morbidity outcome measurement and reporting in trials, studies and clinical practice and will inform future research in this field.
The Importance of Food Processing and Eating Behavior in Promoting Healthy and Sustainable Diets
Authors: Ciarán G. Forde, Eric A. Decker
Journal: Annual Review of Nutrition (2022)

Numerous association studies and findings from a controlled feeding trial have led to the suggestion that "processed" foods are bad for health. Processing technologies and food formulation are essential for food preservation and provide access to safe, nutritious, affordable, appealing and sustainable foods for millions globally. However, food processing at any level can also cause negative health consequences that result from thermal destruction of vitamins; formation of toxins such as acrylamide; or excessive intakes of salt, sugar, and fat. Research on ultraprocessed foods centers on food composition and formulation. In addition, many modern food formulations can have poor nutritional quality and higher energy density. We outline the role of processing in the provision of a safe and secure food supply and explore the characteristics of processed foods that promote greater energy intake. Despite the potential for negative health effects, food processing and formulation represent an opportunity to apply the latest developments in technology and ingredient innovation to improve the food supply by creating foods that decrease the risk of overeating.
Association of baseline corticosteroid treatment with outcomes for patients (pts) with BRAF-mutant melanoma brain metastases (MBMs) in COMBI-MB treated with dabrafenib and trametinib (DT).
Authors: James S. Wilmott, Hiya Banerjee, Philippe Saiag, Caroline Robert, Jean-Jacques Grob, Georgina V. Long, Michael A. Davies
Journal: Journal of Clinical Oncology (2022)

e21546 Background: The COMBI-MB trial showed that DT was safe for BRAF-mutant melanoma pts with MBMs. However, slightly lower intracranial response rates (ICRR) and markedly shorter intracranial progression-free survival (PFS) were observed than in previous trials in pts with extracranial metastases (EM) only. In order to understand the basis of this difference in outcomes, and to inform patient management, we performed post hoc analyses of baseline clinical features to identify associations with ICRR, PFS, and overall survival (OS). Methods: Analyses were performed on all patients (n = 125) enrolled in the COMBI-MB trial. Baseline features included age, gender, ECOG performance status (PS), BRAF genotype (V600E vs V600 other), number of MBM, sum of longest diameters (SLD) of MBMs, maximum MBM size, presence of EM, serum lactate dehydrogenase (LDH), baseline corticosteroid treatment, prior treatments (systemic, radiotherapy to brain, surgery to brain), and presence of uncontrolled MBM symptoms. Univariate (UV) and multivariate (MV, all variables entered) analysis utilized Cox proportional hazards modeling. Associations with ICRR were identified using logistic regression modelling. P values of &gt; 0.05 were considered significant. Results: Corticosteroids treatment at baseline was the only factor associated with ICRR on either UV (p = 0.021) or MV (p = 0.048) analysis. Pts on corticosteroids (n = 13) had an ICRR of 39% versus 63% for patients not on steroids (n = 63) (OR 0.323, 95% CI 0.105-0.996 on MV). Pts receiving corticosteroids also had shorter PFS [median 4.3 versus 6.2 months (mos), HR 1.931, CI 1.061-3.513, P = 0.031 on MV]. BRAF V600E genotype (n = 104, median 5.9 months) was associated with improved PFS versus BRAF V600 other (n = 21, median 4.2 months, HR 0.565, CI 0.321-0.996, P =0.0483 in MV). On UV analysis, OS was associated with elevated LDH (median 10.6 versus 12.7 months, HR 1.595, CI 1.045- 2.434, P = 0.0305), baseline treatment with corticosteroids (median 9.3 versus 13.5 months, HR 1.642, CI 1.037- 2.598, P = 0.0343), and ECOG PS status of 0 (median 18.9 versus 8.2 months, HR 0.435, CI 0.285-0.664). Only ECOG status remained significant on MV of OS (HR 0.441, CI 0.249-0.779, P = 0.0048). Conclusions: Baseline corticosteroid treatment was independently associated with inferior clinical outcomes in MBM pts treated with D+T in COMBI-MB, similar to previous associations reported in immunotherapy trials for pts with MBMs. Likewise, superior outcomes in COMBI-MB patients with BRAFV600E genotype and ECOG status of zero builds on similar observations in COMB-D/V trials of extracranial disease only. The use of corticosteroids to treat symptoms is a major obstacle for the efficacy of systemic treatments for MBMs. Clinical trial information: NCT02039947.
Severe immunosuppression is related to poorer immunogenicity to SARS-CoV-2 vaccines among people living with HIV
Authors: Anaïs Corma-Gómez, Marta Fernández-Fuertes, Estefanía García, Ana Fuentes-López, Cristina Gómez-Ayerbe, Antonio Rivero-Juárez, Carmen Domínguez, Marta Santos, Laura Viñuela, Rosario Palacios, Luis M. Real, Antonio Rivero, Juan Macías, Juan A. Pineda, Federico García
Journal: Clinical Microbiology and Infection (2022)
Phase 1 pilot study with dose expansion of chemotherapy in combination with CD40 agonist and Flt3 ligand in metastatic triple-negative breast cancer.
Authors: Sangeetha M. Reddy, Meredith Carter, Isaac Chan, Melanie Hullings, Nisha Unni, Jessica Medina, Shahbano Shakeel, Susan Armstrong, Lakeisha Cade, Farjana J. Fattah, Chul Ahn, Yisheng V. Fang, Nan Chen, Heather L. McArthur, Nicole Sinclair, Michael Jay Yellin, Joyce O'Shaughnessy, Rita Nanda, Suzanne D. Conzen, Carlos L. Arteaga
Journal: Journal of Clinical Oncology (2022)

TPS1126 Background: Only a subset of patients with metastatic triple-negative breast cancer demonstrate response to currently approved PD-1 immune checkpoint blockade, and few have durable responses. Antigen presentation defects may be a reason for this low response because deficiency of antigen-presenting DC1 dendritic cells is associated with poor anti-tumor immunity. CD40 agonists are a class of agents that activate antigen presenting cells including dendritic cells and B cells and also repolarize macrophages. Flt3 ligand is a growth factor that increases dendritic cells. In line with this, we recently demonstrated in pre-clinical models that the combination of liposomal-doxorubicin chemotherapy, a CD40 agonist, and a Flt3 ligand improves outcomes of breast cancer compared to alternate combinations. Methods: This is a single arm phase I pilot study of liposomal-doxorubicin, CDX-1140 (CD40 agonist), and CDX-301 (Flt3 ligand) combination therapy in patients with metastatic or unresectable locally advanced metastatic triple-negative breast cancer. Patients will be randomized to 3 lead-in arms (triplet therapy, doublet immunotherapy only, liposomal-doxorubicin only) prior to receiving full triplet therapy with fresh tissue biopsies before and after the lead-in treatment. CDX-301 will be discontinued after 2 cycles; liposomal-doxorubicin and CDX-1140 will be continued until disease progression or clinically limiting toxicities. Primary endpoint is determination of a recommended phase 2 dose based on treatment-related adverse events including dose-limiting toxicities. Secondary endpoints include anti-tumor immune response after triplet therapy, after immunotherapy alone, and after liposomal-doxorubicin alone; median progression-free survival, overall response rate, duration of response, and clinical benefit rate. Key eligibility criteria are unresectable stage III or stage IV triple-negative breast cancer (ER ≤10%, PR ≤10%, HER2/neu negative), 1 st to 3 rd line metastatic treatment setting (1 st line patients need to be PD-L1 negative by 22C3 assay), measurable disease by RECIST 1.1 criteria, consent for pre-treatment and on-treatment biopsies of amenable soft tissue tumor lesions, no prior treatment with an anti-CD40 antibody or a Flt3 ligand, no anthracycline treatment in the metastatic setting, no prior progression while on anthracycline-based therapy or within 6 months of completing neoadjuvant chemotherapy, and no history of non-infectious pneumonitis or current pneumonitis. This trial will enroll up to 45 patients across multiple sites. Clinical trial information: NCT05029999.
Benefit of lymph node dissection in cn+ patients in the treatment of upper tract urothelial carcinoma: Analysis of ncdb registry
Authors: A.J. Piontkowski, N. Corsi, S. Morisetty, S. Majdalany, I. Rakic, S. Arora, M. Jamil, D. Dalela, C. Rogers, F. Abdollah
Journal: European Urology (2022)